Influenza, commonly referred to as flu, is an infectious disease caused by RNA viruses of the family Orthomyxoviridae (the influenza viruses). Influenza spreads around the world in seasonal epidemics, resulting in the deaths of between 200,000 and 500,000 to people every year, up to millions in some pandemic years. The development of effective antiviral medicines is hampered by the exceptionally high mutation rates of influenza virus. Therefore, in order to be successful, new drugs should target the molecular mechanisms specific to the proliferation of the virus.
H5N1 and H1N1 strains of virus have shown pandemic disease threat worldwide and has been the cause of death of thousands of people till date by viral flu. These viruses actually cut surface protein of infected host cell and allow spreading to other cell. Oseltamivir phosphate (1, Tamiflu, Ro 64-0796, GS4104) and Zanamivir (2, Relenza, GG 167) are currently used as neuraminidase inhibitor drugs. Oseltamivir phosphate is recommended as the best choice due to its oral active form and bioavailability (FIG. 1). The anti-influenza drug 1 was initially discovered by Gilead Sciences and subsequently licensed to Roche for production from (−)-shikimic acid. It has inevitably increased the demand of tamiflu due to threat of avain and seasonal influenzas. There is huge pressure on raw materials supply to meet worldwide demand of tamiflu.

Currently manufacturing process for tamiflu uses (−)-shikimic acid as the raw material. The insufficient quantities of (−)-shikimic acid either by extraction from its natural sources, fermentation or chemical synthesis is a drawback in meeting the demands. Thus far the unabated efforts of chemical community have devised many alternative syntheses of seemingly simple but synthetically challenging molecule tamiflu, utilizing readily available and inexpensive starting materials. There is still requirement of the synthesis of 1, where the use of azide and aziridine intermediate should be avoided to minimize the hazard and complexity in the synthesis.
Article titled “Two approaches toward the formal total synthesis of oseltamivir phosphate (Tamiflu): catalytic enantioselective three-component reaction strategy and L-glutamic acid strategy” by K Alagiri et al. published in J Org Chem, 2013 Apr. 19, 78(8):4019-26 reports two independent formal total syntheses of oseltamivir phosphate were successfully achieved: the first utilized a copper-catalyzed asymmetric three-component reaction strategy, and the second utilized L-glutamic acid γ-ester as a chiral source to install the correct stereochemistry. Both strategies used Dieckmann condensation to construct a six-membered ring core, after which manipulation of the functional groups and protecting groups accessed Corey's intermediate for the synthesis of oseltamivir phosphate. While the first synthesis was accomplished via four purification steps in 25.7% overall yield, albeit with moderate optical purity (76% ee), the second strategy achieved the synthesis via six purification steps in 19.8% overall yield with perfect enantiocontrol.
Article titled “Efficient Formal Synthesis of Oseltamivir Phosphate (Tamiflu) with Inexpensive d-Ribose as the Starting Material” by H Osato et al. published in Org. Lett., 2010, 12 (1), pp 60-63 reports an efficient formal synthesis of oseltamivir phosphate (Tamiflu) has been achieved in 12 steps with use of the inexpensive and highly abundant d-ribose as the starting material. This concise alternative route does not utilize protecting groups and features the introduction of 3-pentylidene ketal as the latent 3-pentyl ether, the use of a highly efficient RCM reaction to form the Tamiflu skeleton, and selective functional group manipulations.
Article titled “A Practical and Azide-Free Synthetic Approach to Oseltamivir from Diethyl d-Tartrate” by J Weng et al. published in J. Org. Chem., 2010, 75 (9), pp 3125-3128 reports a short and practical synthesis of oseltamivir was accomplished in 11 steps from inexpensive and abundant diethyl d-tartrate starting material. This azide-free route featured an asymmetric aza-Henry reaction and a domino nitro-Michael/Horner-Wadsworth-Emmons (HWE) reaction as the key steps to construct the relevant cyclohexene ring of the product, which provided an economical and practical alternative for the synthesis of oseltamivir.
Article titled “Ring-closing metathesis-based synthesis of (3R,4R,5S)-4-acetylamino-5-amino-3-hydroxy-cyclohex-1-ene-carboxylic acid ethyl ester: a functionalized cycloalkene skeleton of GS4104” by X Cong et al. published in J Org Chem, 2006 Jul. 7; 71(14), 5365-8 reports (3R,4R,5S)-4-Acetylamino-5-amino-3-hydroxy-cyclohex-1-ene-carboxylic acid ethyl ester, a functionalized cyclohexene skeleton of GS4104, was diastereoselectively synthesized. A major advantage of this synthesis is the use of readily available L-serine to replace frequently used (−)-shikimic acid or (−)-quinic acid as the starting material. Ring-closing metathesis and diastereoselective Grignard reactions successfully served as the key steps. Absolute configurations of the key intermediates were confirmed by corresponding two-dimensional NMR studies.
Article titled “Novel asymmetric synthesis of oseltamivir phosphate (Tamiflu) from (−)-shikimic acid via cyclic sulfite intermediates” by L D Nie et al. published in Tetrahedron: Asymmetry, Volume 22, Issues 16-17, 15 Sep. 2011, Pages 1692-1699 reports a novel asymmetric synthesis of oseltamivir phosphate 1 from the naturally abundant (−)-shikimic acid via 3,4-cyclic sulfite intermediate 3 (FIG. 2) is described. Target compound 1 was obtained in 39% overall yield from this nine-step synthesis, and the characteristic step of the synthesis is the regio- and stereospecific nucleophilic substitution with sodium azide at the allylic (C-3) position of 3,4-cyclic sulfite 3. Since the yield of the direct-aziridine-formation from the unprotected dihydroxyl azide 4 was not satisfactory, two improved preparations of the established compound 7 via protected 3,4-cyclic sulfites 10 and 13 (FIG. 3) have been developed. In these two improved preparations, compound 7 was obtained from 3,4-cyclic sulfite 3 in 7-steps in 64% or 62% overall yield, respectively.